The present invention relates to a novel and improved process for preparation of d-2-(6-methoxy-2-naphthyl) propionic acid of formula (I) by means of a asymmetric synthesis method. ##STR1##
In d-and 1-enantiomers of 2-(6-methoxy-2-naphthyl) propionic acid, particularly d-isomers can be used as nonsteriod antipyretic analgesics having an excellent anti-inflammatory, analgesic and antipyretic effects.
The general processes which are concerned with the present invention are described in U.S. Pat. Nos. 3,651,106, 3,652,683, 3,658,858, 3,658,863, 3,663,584, 3,686,238, and 3,683,015. According to these known processes d-isomers may be separated by preparing racemic mixtures of 2-(6-methoxy-2-naphthyl)propionic acid and by using alkaloid such as (+)-cinchonine, (-)-cinchonine and like.
Unlike the conventional process separating d-isomers from the racemic mixtures of 2-(6-methoxy-2-naphthyl) propionic acid, the present invention is characterized in that only d-isomers are selectively prepared by means of method of asymmetric synthesis using oxazolidinone compounds having the following formula (II) as a chiral auxiliary: ##STR2##
Wherein R.sup.1 is C.sub.1-8 alkyl or C.sub.6-12 aryl of such as, for example, methyl, isopropyl, secondarybutyl tert-butyl, benzyl, phenyl group and like. R.sup.2 is H, C.sub.1-8 alkyl or C.sub.6-12 aryl such as, for example, hydrogen, phenyl group. Also, wherein the absolute structure of chiral carbon atom (s) which is neighbouring to R.sup.1 is (S), when R.sup.2 is not hydrogen atom (S), the absolute structure of the neighbouring chiral carbon atom, (S) is (R).
A method of the asymmetric synthesis of d-substituted carboxylic acid derivatives can be found in the literature [J. Am. Chem. Soc. 104 (1982) 1737]. Accordingly, novel process for preparing compounds of general formula (I) in accordance with the present invention may be not necessary a complicated and combersome process for separating the existing d-and 1-isomers or the racemization process for reusing an undesirable 1-isomers. Thus, the present invention is economical and provides a novel and improved process for preparing.
Explaining now in detail the present invention, it is beginning by reacting oxazolidinone of formula (I) as a starting material with 6-methoxy-2-naphthylacet chrolide. Oxazolidinone of formula (II) is obtained by reacting p-aminoalcohol having optical activities which can be easily obtained from the natural substance, such as (S)-valinol (1R, 2S)-norephedrine (S)-phenylglycinol, (S)-allaninol, (S)-phenylallaninol, (S)-leucinol, (S)-isoleucinol, (S)-tert-leucinol and the like with phosgene or diethylcarbonate and the like. The detailed contents regarding to a process for preparing compounds of formula (II) are described fully in the literature [J. Am. Chem. Soc. 73 (1951) 4199].
6-methoxy-2-naphthylacetehloride of formula (III) is obtained by reacting 6-methoxy-2-naphthylacetic acid of formula (III) with from 1 to 3 molar equivalents of thionyl chloride phosphorus tribromide oxalyl chloride and the like in a solvent such as benzene, diethylether, tetrahydrofuran, dichloromethane.
After terminating the reaction, the compound of formula (IV) is not separated and the solvent and the residual excess of halogenation reagent is only evaporated and removed and then used for the following reaction. The preferred halogenation reagent is oxallylchloride and the reaction is terminated by stirring the oxallyl chloride with the compound of formula (III) in the solvent such as tetrahydrofuran less than 24 hours at a room temperature.
After the metal solt of the compound of formula (II) is obtained by reacting the compound of formula (II) with the same equivalent of n-buthyllithium or sodium hydride and the like, novel [N-(6-methoxy-2-naphthyl)acethyl]-oxazolidinone compound is obtained by reaction of the resultant metal salt with the same equivalent of the compound of formula (IV) in succession.
In this case, suitable solvents include benzene, toluene, diethylether, tetrahydrofuran and the like, the reaction temperature is at a temperature of from about -30.degree. to 20.degree. C.
Novel [N-(2s)-2-(6-methoxy-2-naphthyl)-propionyl]-oxazolidinone compound of formula (VI), after reacting [N-(6-methoxy-2-naphthyl)acethyl]-oxazolidinone compound of formula (V) with the same equivalent of a base such as lithiumisopropylamide or sodium bistrimethylsilylamide and a like at the temperature of the range from -80.degree. C. to 0.degree. C., is obtained by reacting the resultant reaction solution with an excess of quantity of methane iodide or dimethyl sulfate. The yield of the compound of formula (VI) is more than 90%, and the optical yield is also more than 98%. ##STR3##
When d-2-(6-methoxy-2-naphthyl)propionic acid of formula (I) is prepared from [N-(2s)-2-(6-methoxy-2-naphthyl)-propionyl]oxazolidinone compound of formula (VI), the acid can be prepared by two methods, the one method being obtained by reacting the compound of formula (VI) directly in the alkali metal hydroxide and alcohol water solution and the like at the temperature from -30.degree. to 10.degree. C. for 1 hour, the other method being prepared the ester compound of formula (VI) by reacting the compound of formula (VI) with alkali metal alkoxide and the like at the temperature of -30.degree. C. to 10.degree. C. for 1 hour acid then obtaining the compound of formula (I) from these ester compounds. The resultant compound of formula (I) have the optical purity of more than 99%, and particularly oxazolidinone compound of formula (II) used as chirol auxiliary is not dissolved and not racemated thereby completly being recovered. ##STR4##
As described above, the present invention provides a novel and improved process which can prepare the compounds of formula (I) in very high yield by way of novel compounds of formulas (V) and (VI) and selectively through simple stages, otherwise than the previous processes according to the separation process of d, 1-isomers.
In order to promote understanding of the present invention, the reaction scheme for preparting d-2-(6-methoxy-2-naphthyl)propionic acid is represented as follow. ##STR5##
Referring to the examples, the present invention is explained in detail as follows;
The following reactions were proceeded under the nitrogen air, unless otherwise mentioned.